Amphiphilic Cyclodextrin Nanoparticles as Delivery System for Idebenone: A Preformulation Study.

Idebenone (IDE), a synthetic short-chain analogue of coenzyme Q10, is a potent antioxidant able to prevent lipid peroxidation and stimulate nerve growth factor. Due to these properties, IDE could potentially be active towards cerebral disorders, but its poor water solubility limits its clinical application. Octanoyl-ß-cyclodextrin is an amphiphilic cyclodextrin (ACyD8) bearing, on average, ten octanoyl substituents able to self-assemble in aqueous solutions, forming various typologies of supramolecular nanoassemblies. Here, we developed nanoparticles based on ACyD8 (ACyD8-NPs) for the potential intranasal administration of IDE to treat neurological disorders, such as Alzheimer's Disease. Nanoparticles were prepared using the nanoprecipitation method and were characterized for their size, zeta potential and morphology. STEM images showed spherical particles, with smooth surfaces and sizes of about 100 nm, suitable for the proposed therapeutical aim. The ACyD8-NPs effectively loaded IDE, showing a high encapsulation efficiency and drug loading percentage. To evaluate the host/guest interaction, UV-vis titration, mono- and two-dimensional NMR analyses, and molecular modeling studies were performed. IDE showed a high affinity for the ACyD8 cavity, forming a 1:1 inclusion complex with a high association constant. A biphasic and sustained release of IDE was observed from the ACyD8-NPs, and, after a burst effect of about 40%, the release was prolonged over 10 days. In vitro studies confirmed the lack of toxicity of the IDE/ACyD8-NPs on neuronal SH-SY5Y cells, and they demonstrated their antioxidant effect upon H2O2 exposure, as a general source of ROS.

Enhanced Cellular Uptake Of Phenamil Through Inclusion Complex With Histidine Functionalized ß-Cyclodextrin As Penetrative Osteoinductive Agent.

BACKGROUND: Phenamil (PH) is a small molecule that induces bone formation through upregulation of the TRB3 gene in the bone-regeneration process. ß-Cyclodextrins (ßCDs) with hydrophilic surfaces and a relatively hydrophobic cavity can form inclusion complexes with primarily hydrophobic small molecules such as PH, and increase their apparent solubility and dissolution rate. The hydrophilic surface of ßCDs prevents their interaction with the hydrophobic lipids of the cell membrane for penetration. Therefore, binding of penetrative groups, such as lysine, arginine, and histidine (His), to ßCDs for cell penetration is required. AIM: The aim of this study was to investigate the effect of His-conjugated ßCD on cellular uptake of PH for bone differentiation. METHODS: In this study, His-ßCDs were synthesized and used to prepare an inclusion complex of His-ßCD-PH. A hydroxypropyl-ßCD-PH (HP-ßCD-PH) inclusion complex for increasing PH solubility without a penetrative group was prepared for comparison. 3-D geometry of ßCD derivatives and PH-inclusion complexes was investigated by Fourier-transform infrared spectroscopy and molecular docking. Alizarin red staining and real-time PCR were performed to compare bone differentiation of His-ßCD-PH and HP-ßCD-PH. RESULTS: The results suggested that the benzene ring of PH was inserted into the wide side of both His-ßCD and HP-ßCD. Alizarin red staining at 14 days postculture in the presence of His-ßCD-PH at total concentration of 50 µM for PH showed that bone-matrix mineralization increased significantly compared with free PH and HP-ßCD-PH. Real-time PCR confirmed this result, and showed gene expression increased significantly (OPN 1.84-fold, OCN 1.69-fold) when stem cells were cultured with His-ßCD-PH. CONCLUSION: The overall results indicated that His-ßCD-PH is a promising carrier for osteoinductive PH with possible penetration ability and sustained release that reduces BMP2 consumption for differentiation of mesenchymal stem cells to bone tissue.

ß-Cyclodextrin-dextran polymers for the solubilization of poorly soluble drugs.

The aim of this study was to assess the potential of novel ß-cyclodextrin (ßCD)-dextran polymers for drug delivery. The size distribution of ßCD-dextrans (for eventual parenteral administration), the influence of the dextran backbones on the stability of the ßCD/drug complex, the solubilization efficiency of poorly soluble drugs and drug release properties were investigated. Size analysis of different ßCD-dextrans was measured by size exclusion chromatography (SEC) and asymmetrical flow field-flow fractionation (AF4). Stability of drug/ßCD-dextrans was assessed by isothermal titration calorimetry (ITC) and molar enthalpies of complexation and equilibrium constants compared to some commercially available ßCD derivatives. For evaluation of the solubilization efficiency, phase-solubility diagrams were made employing hydrocortisone (HC) as a model of poorly soluble drugs, whereas reverse dialysis was used to detect potential drug supersaturation (increased molecularly dissolved drug concentration) as well as controlled release effects. Results indicate that all investigated ßCD-polymers are of appropriate sizes for parenteral administration. Thermodynamic results demonstrate that the presence of the dextran backbone structure does not affect the stability of the ßCD/drug complex, compared to native ßCD and commercially available derivatives. Solubility studies evidence higher solubilizing abilities of these new polymers in comparison to commercially available ßCDs, but no supersaturation states were induced. Moreover, drug release studies evidenced that diffusion of HC was influenced by the solubilization induced by the ßCD-derivatives.